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WO2025057985A1 - Dispositif capable de mesurer simultanément une force contractile spécifique du myocarde et un potentiel d'activité - Google Patents

Dispositif capable de mesurer simultanément une force contractile spécifique du myocarde et un potentiel d'activité Download PDF

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Publication number
WO2025057985A1
WO2025057985A1 PCT/JP2024/032578 JP2024032578W WO2025057985A1 WO 2025057985 A1 WO2025057985 A1 WO 2025057985A1 JP 2024032578 W JP2024032578 W JP 2024032578W WO 2025057985 A1 WO2025057985 A1 WO 2025057985A1
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Prior art keywords
myocardial tissue
contractile
cardiomyocytes
contractile force
measuring
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English (en)
Japanese (ja)
Inventor
莉 劉
俊君 李
繁 宮川
芳樹 澤
真季 武田
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Cuorips Inc
University of Osaka NUC
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Osaka University NUC
Cuorips Inc
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M1/00—Apparatus for enzymology or microbiology
    • C12M1/34—Measuring or testing with condition measuring or sensing means, e.g. colony counters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material

Definitions

  • the present invention relates to artificial myocardial tissue, its use, and its manufacturing method.
  • the most common methods for evaluating the function of cardiomyocytes to date are the action potential measurement method using multi-electrodes and the contractile force measurement method using cell motion and electrical resistance.
  • the multi-electrode array used to measure the action potential has the following drawbacks: (1) The adhesion between the multi-electrode chip and the cells is weak, and the cells are uneven and prone to clumping, and are easily peeled off from the electrode chip. This causes the propagation direction of the excitation of the electrical signal to be inconsistent when pacing, and the addition of drugs frequently causes arrhythmia. In addition, cells cannot be cultured for long periods on the multi-electrode.
  • Cardiomyocytes on the multi-electrode chip have a random structure and do not have the original myocardial orientation structure.
  • (3) Although it is possible to measure two-dimensional (2D) cardiomyocytes, it is not possible to measure thick myocardial tissue.
  • the cell motion imaging and electrical resistance methods most commonly used to measure the contractile force of cardiomyocytes are suitable for evaluating the contractile force of myocardium by analyzing the pulsation behavior of 2D cardiomyocytes, but are not applicable to three-dimensional (3D) myocardial tissue with a thick orientation structure.
  • the objective of the present invention is to provide a device that can simultaneously measure electrical signals and contractile force using highly mature myocardial tissue that has a 3D, oriented structure similar to the myocardial structure in vivo.
  • the inventors conducted intensive research to solve the above problems, and discovered that by designing a device having a three-dimensional structure and a contractile part including rod-shaped artificial myocardial tissue in which cardiomyocytes are oriented in the longitudinal direction so as to be able to measure the contractile force of the contractile part, it is possible to provide a device for measuring the contractile force of highly mature myocardial tissue having a structure similar to that of the myocardial structure in a living body. Such a device can be easily designed so that electrical signals can be measured simultaneously.
  • the present invention was completed through further research based on this knowledge, and includes the following aspects.
  • Item 1 A device for measuring the contractile force of myocardial tissue, comprising a contractile section having a three-dimensional structure and including rod-shaped artificial myocardial tissue in which cardiomyocytes are oriented in the longitudinal direction, and used to measure the contractile force of the contractile section.
  • Item 2. Item 2. The device for measuring the contractile force of myocardial tissue according to item 1, wherein the artificial myocardial tissue is obtained by culturing myocardial cells on a surface having a contact angle with water of 95° or more.
  • Item 3. moreover, a marker portion including non-contractile myocardial tissue; Item 3.
  • Item 4. moreover, Item 4.
  • a method for producing a rod-shaped artificial myocardial tissue having a three-dimensional structure and in which cardiomyocytes are oriented in the longitudinal direction comprising: A method for producing the artificial myocardial tissue, comprising the step of culturing cardiomyocytes on a surface having a contact angle with water of 95° or more to obtain the artificial myocardial tissue. Item 6. Item 6.
  • the method for producing a rod-shaped artificial myocardial tissue according to Item 5 wherein in the step, an area (A) having a surface with a contact angle to water of 95° or more is bonded to two areas (B) having surfaces with a contact angle to water of 85° or less, and by culturing cardiomyocytes in the areas (A) and (B), the rod-shaped artificial myocardial tissue is formed on a line connecting the two areas (B).
  • the present invention provides a device for measuring the contractile force of mature myocardial tissue that has a structure similar to that of the myocardial structure in vivo. Such a device can be easily designed to simultaneously measure electrical signals.
  • FIG. 1 is a schematic diagram of an example of a device for measuring contractile force.
  • 1 is a photograph of an example of a device for measuring contractile force.
  • FIG. 2 is a schematic diagram illustrating the measurement principle of a device for measuring contractile force.
  • 1 is an example of a measurement result using a contractile force measuring device.
  • 1 shows an example of the measurement results using a contractile force measuring device (effect of E4031 addition).
  • 1 is an example of a measurement result using a device for measuring contractile force (effect of addition of verapamil).
  • 1 shows an example of the measurement results using a device for measuring contractile force (evaluation of drug response using normal and diseased iPS cell-derived cardiomyocytes).
  • FIG. 1 is a schematic diagram showing an example of an application of a device for measuring contractile force.
  • 1 is a photograph showing the results of measuring the contact angles of various materials with water.
  • 1 is a graph showing the results of measuring the contact angles of various materials with water.
  • the device for measuring contractile force of myocardial tissue of the present invention is It has a three-dimensional structure and is provided with a contractile portion including a rod-shaped artificial myocardial tissue in which cardiomyocytes are oriented in the longitudinal direction, and is used to measure the contractile force of the contractile portion.
  • the device for measuring the contractile force of myocardial tissue of the present invention includes rod-shaped artificial myocardial tissue in which the contractile part has a three-dimensional structure and the cardiomyocytes are oriented in the longitudinal direction, and is capable of measuring the contractile force of this contractile part. This makes it possible to measure the contractile force of highly mature myocardial tissue that has a structure similar to that of the myocardial structure in a living body. Furthermore, as described below, such a device can be easily designed to simultaneously measure electrical signals.
  • the artificial myocardial tissue can be obtained by culturing cardiomyocytes on a surface with a contact angle of 95° or more with respect to water.
  • an area (A) having a surface with a contact angle of 95° or more with respect to water is bonded to two areas (B) that allow non-oriented culture, and by culturing cardiomyocytes in the areas (A) and (B), the rod-shaped artificial myocardial tissue is formed on the line connecting the two areas (B).
  • both ends of the strip in the long axis direction are bonded to a substrate (b) with a surface having a water contact angle of 85° or less, and cardiomyocytes are cultured in suspension on the strip using a liquid medium, the cardiomyocytes will first tend to gather on the substrates (b) at both ends, forming a cardiomyocyte cell population at that site.
  • the adhesiveness of the long and thin strip (a) with a surface having a water contact angle of 95° or more is weak, so cardiomyocytes are less likely to accumulate compared to the substrates (b) at both ends.
  • the inventors have found that by continuing the culture, the cardiomyocytes gradually accumulate in the central part of the long and thin strip (a) along the long axis direction, bridging the cardiomyocyte populations at both ends, forming a rod-shaped artificial myocardial tissue oriented in the long axis direction.
  • the inventors have confirmed that this rod-shaped artificial myocardial tissue has a three-dimensional structure, the cardiomyocytes are oriented in the long axis direction, and is a highly mature myocardial tissue with a structure similar to that in vivo.
  • the contact angle of the surface with water temporarily drops to 85° or less, and therefore cardiomyocytes tend to accumulate on the entire surface of the elongated piece (strip) (a) immediately after culturing begins.
  • the effect of the plasma treatment weakens and the contact angle of the surface with water gradually returns to the value before plasma treatment, so that cardiomyocytes gradually accumulate in the central part of the elongated piece (strip) (a), as described above.
  • a surface with a contact angle with water of 95° or more is preferable if it has a contact angle with water of 100° or more, and more preferable if it has a contact angle with water of 105° or more, in that artificial myocardial tissue can be obtained efficiently.
  • this surface is preferable if it has a contact angle with water of 120° or less, more preferable if it has a contact angle with water of 115° or less, and even more preferable if it has a contact angle with water of 110° or less.
  • a surface with a contact angle of 95° or more with water may be made of any material as long as the contact angle with water is within the above range, and examples include silicone (silicon resin), with PDMS (polydimethylsiloxane), silicone rubber, etc. being particularly preferred.
  • the substrate (b) has a surface with a contact angle with water of 85° or less, and from the viewpoint of efficient production of artificial myocardial tissue, it is preferable that the contact angle with water is 80° or less, more preferably 75° or less, and even more preferably 70° or less. In addition, from the viewpoint of efficient production of artificial myocardial tissue, it is preferable that the contact angle with water of the substrate (b) is 50° or more, and more preferably 60° or more.
  • the substrate (b) has the above-mentioned contact angle with respect to water and can be selected from a wide range of materials known to be suitable for cell culture. Examples include polyimine, polyethylene terephthalate, polyethyleneimine, polystyrene, and glass. Oriented fibers, which will be described later, may also be used as substrate (b). In this case, the artificial myocardial tissue formed in the region can be oriented.
  • the contact angle of water is determined by shining light onto a droplet on the surface to be measured, capturing an image of the droplet from the opposite side with a camera, and calculating it through image analysis.
  • the rod-shaped artificial myocardial tissue highly expresses ⁇ -MHC, which is a maturation marker.
  • ⁇ -MHC which is a maturation marker.
  • whether or not myocardial tissue highly expresses ⁇ -MHC can be confirmed by immunohistochemical staining.
  • the rod-shaped artificial myocardial tissue has a width in the direction of the culture surface of preferably 0.03 to 30 mm, more preferably 0.1 to 10 mm, and even more preferably 0.3 to 3 mm, from the viewpoint of convenience in measuring the contractile force.
  • the rod-shaped artificial myocardial tissue has a width in the direction perpendicular to the culture surface of preferably 0.003 to 30 mm, more preferably 0.03 to 3 mm, and even more preferably 0.1 to 1 mm.
  • cardiomyocytes can be selected appropriately depending on the purpose of the measurement. For example, when used to evaluate the cardiotoxicity of drugs, etc., cardiomyocytes derived from normal human iPS cells can be used. Furthermore, when used for drug development, cardiomyocytes derived from iPS cells with heart disease can also be used as necessary.
  • FIG. 3 As an example of a specific configuration of the device for measuring the contractile force of myocardial tissue of the present invention, as shown in Figure 3, there is a configuration in which a base material having a hollow area around the contractile part is provided at the bottom. This configuration has the advantage that the contractile part is likely to be in a floating state, making it easier to measure the contractile force. Furthermore, if necessary, a configuration in which the periphery is surrounded by a partition member can be adopted, as shown in Figure 3.
  • the material of the member having a cavity is not particularly limited, but examples include polyethylene terephthalate, polyethyleneimine, and polystyrene.
  • the purpose of the partition member is to prevent the liquid medium from leaking out, and as long as this purpose is achieved, the shape is not particularly limited, but it can be, for example, a ring-shaped member.
  • the material of the partition member is not particularly limited, but examples include PDMS (polydimethylsiloxane), polystyrene, silicone rubber, and glass.
  • the device for measuring the contractile force of myocardial tissue of the present invention further comprises: a marker portion including non-contractile myocardial tissue;
  • the contraction portion may be coupled to the marker portion such that the contractile force of the contraction portion is measurable depending on the mobility of the marker portion.
  • the contraction part and marker part are suspended in a liquid medium, and when the myocardium pulsates, the movement distance of the floating marker part is detected using image recognition technology, the magnitude of the movement vector and its change over time are recorded, and the contraction force can be measured by recalculating and converting it into force.
  • the measurement of contractile force based on the movement distance of the marker can be performed, for example, as follows.
  • a device called “MicroTester” Cell Scale
  • the sensor in contact with the tissue moves with the myocardial pulsation, so the movement distance of the sensor is recorded as a video.
  • the "MUSCLEMOTION” plugin of the free software "ImageJ” is used to obtain displacement curves of the sensor at different times.
  • this information is used to convert into intracellular forces that the sensor experiences at different times.
  • such a marker portion may include myocardial tissue formed in region (B) having a surface with a contact angle with water of 85° or less.
  • non-contractile myocardial tissue means that the contractility is lower than that of the rod-shaped artificial myocardial tissue of the contractile portion, and does not necessarily mean that the tissue has no contractility at all. This is because the orientation of the cardiomyocytes is lower than that of the rod-shaped artificial myocardial tissue of the contractile portion.
  • the device for measuring the contractile force of myocardial tissue of the present invention further comprises:
  • the device may include an action potential measuring unit having a three-dimensional structure and including an artificial myocardial tissue in which cardiomyocytes are oriented, and the action potential measuring unit may be used for action potential measurement using multiple electrodes. This makes it possible to provide a device that can simultaneously measure an electrical signal and a contractile force.
  • an existing multi-electrode system for measuring electrical signals can be applied, and part of the device can be attached to a multi-electrode chip to measure action potentials.
  • an artificial myocardial tissue having a three-dimensional structure of the action potential measurement section and oriented cardiomyocytes there is no particular limitation on the method of obtaining an artificial myocardial tissue having a three-dimensional structure of the action potential measurement section and oriented cardiomyocytes.
  • it can be obtained by culturing cardiomyocytes using oriented fibers as a scaffold for the cells (J. Li et al., 2017 Stem Cell Reports, 9, 1-14, 2017).
  • the oriented fiber for example, one obtained by electrospinning using a polymer as a raw material can be used.
  • the polymer can be any one that does not adversely affect the proliferation and physiological activity of cardiomyocytes, and can be selected from a wide range of polymers depending on the purpose of use. Examples include polylactic acid-co-glycolic acid (PLGA), polylactic acid (P L A), polystyrene (PS), polyethylene terephthalate (PET), gelatin, collagen, etc.
  • the diameter of the oriented fiber is not particularly limited, but can be, for example, 0.1 to 10 ⁇ m, preferably 1 to 8 ⁇ m, and more preferably 3 to 5 ⁇ m.
  • the number of fibers (density) per mm of width in the short axis direction (direction perpendicular to the orientation direction) of the oriented fiber can vary depending on the diameter of the fiber used.
  • the density is 10 fibers/mm or more, preferably 30 to 15,000 fibers/mm, and more preferably 50 to 13,000 fibers/mm.
  • a device having one set each of the contraction section and the action potential measurement section can be sized to fit into one well of a multi-well microplate (e.g., 24-well, 48-well, or 96-well plates are commonly used), and multiple units of the device can be connected together so that each is accommodated in a different well of the multi-well microplate, making it possible to simultaneously measure multiple unit devices using a commonly used multi-well microplate.
  • a multi-well microplate e.g., 24-well, 48-well, or 96-well plates are commonly used
  • the method for producing rod-shaped artificial myocardial tissue of the present invention includes the steps of:
  • the method includes a step of obtaining the artificial myocardial tissue by culturing cardiomyocytes on a surface having a contact angle with water of 95° or more.
  • the culture method is not particularly limited, and can be appropriately selected from among known methods for culturing cardiomyocytes.
  • Culture can be performed in a stationary state or with shaking.
  • an area (A) having a surface with a contact angle to water of 95° or more is bonded to two areas (B) having a surface with a contact angle to water of 85° or less, and the rod-shaped artificial myocardial tissue may be formed on a line connecting the two areas (B) by culturing cardiomyocytes in the areas (A) and (B).
  • This process makes it possible to manufacture the above-mentioned device for measuring the contractile force of myocardial tissue having a marker portion including non-contractile myocardial tissue.
  • Fiber Sheet Processing PLGA 75/25; Sigma-Aldrich, USA
  • HFIP hexafluoro-2-propanol
  • NF-103 MECC, Fukuoka, Japan
  • NF-103 automatic fiber preparation device
  • An aluminum foil sheet was placed on the surface of the drum.
  • the drum rotated at a speed of 1000 rpm, and the PLGA fibers that came out of the needle were collected on the aluminum foil sheet.
  • the distance between the needle tip and the drum was kept at 15 cm, and the spinning process was set for 60 min.
  • the fiber sheet collected on the aluminum foil was then transferred to the device.
  • the fibers were evaluated by observing them with a scanning electron microscope.
  • a PET sheet (SFL-A4, AS ONE) was cut into a disk using a biopsy punch with a diameter of 8 mm, and two 2 mm holes were drilled in the disk to attach the PDMS strip and fiber sheet.
  • the PDMS ring and PET disk were attached.
  • the fiber sheet was transferred to a PET disk using an adhesive transfer tap (3M®).
  • the PDMS strip was moved to attach to the PET disk with tweezers.
  • a polyimide (PI) sheet (3-1966-06, AS ONE) was punched with a 1 mm biopsy punch to create a disk.
  • the disk was attached to the PDMS strip to create a force sensor (device for measuring contraction force) ( Figure 1). Before seeding the cells, the device was treated with plasma for 2 min.
  • the present invention utilizes three-dimensional, oriented fiber technology to construct myocardial tissue with a three-dimensional, oriented structure. It also applies an existing multi-electrode system for measuring electrical signals, and adheres part of the device to a multi-electrode chip to measure action potentials. Furthermore, a part of the device is suspended, and when the myocardium beats, the distance traveled outside the round circle of the suspended part is detected using image recognition technology, the magnitude of the movement vector and changes over time are recorded, and this is converted into force and recalculated ( Figures 2-4).
  • the cells used for measurement are not always the same. As shown below, using the device created in this invention, under the same conditions and using the same cardiomyocytes, we were able to simultaneously measure the changes in electrical signals and contractile force due to the addition of drugs.
  • Verapamil is an antiarrhythmic drug that blocks calcium channels.
  • the pulsation frequency gradually increased, and when the concentration reached 10 ⁇ M, the action potential stopped.
  • the contractile force gradually weakened, becoming almost unmeasurable at a concentration of 1 ⁇ M ( Figure 6).

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Abstract

La présente invention aborde le problème de la fourniture d'un dispositif pour mesurer simultanément un signal électrique et une force contractile en utilisant un tissu myocardique hautement mature ayant une structure orientée/3D proche de la structure myocardique dans un corps vivant. En tant que solution, l'invention concerne un dispositif de mesure de la force contractile d'un tissu myocardique, le dispositif comprenant une unité contractile qui comprend un tissu myocardique artificiel en forme de tige ayant une structure tridimensionnelle et dans lequel des cardiomyocytes sont orientés dans la direction longitudinale, le dispositif étant utilisé pour mesurer la force contractile de l'unité contractile.
PCT/JP2024/032578 2023-09-12 2024-09-11 Dispositif capable de mesurer simultanément une force contractile spécifique du myocarde et un potentiel d'activité Pending WO2025057985A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140220555A1 (en) * 2011-10-12 2014-08-07 The Trustees Of The University Of Pennsylvania In vitro microphysiological system for high throughput 3d tissue organization and biological function
WO2016060260A1 (fr) * 2014-10-16 2016-04-21 国立大学法人京都大学 Fragment de tissu
US20180044640A1 (en) * 2015-05-15 2018-02-15 Agency For Science, Technology And Research Contractile cellular construct for cell culture
US20220315902A1 (en) * 2015-05-11 2022-10-06 The Trustees Of Columbia University In The City Of New York Engineered adult-like human heart tissue

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140220555A1 (en) * 2011-10-12 2014-08-07 The Trustees Of The University Of Pennsylvania In vitro microphysiological system for high throughput 3d tissue organization and biological function
WO2016060260A1 (fr) * 2014-10-16 2016-04-21 国立大学法人京都大学 Fragment de tissu
US20220315902A1 (en) * 2015-05-11 2022-10-06 The Trustees Of Columbia University In The City Of New York Engineered adult-like human heart tissue
US20180044640A1 (en) * 2015-05-15 2018-02-15 Agency For Science, Technology And Research Contractile cellular construct for cell culture

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ELLIS MORGAN E., HARRIS BRYANA N., HASHEMI MOHAMMADJAFAR, HARVELL B. JUSTIN, BUSH MICHAELA Z., HICKS EMMA E., FINKLEA FERDOUS B., : "Human Induced Pluripotent Stem Cell Encapsulation Geometry Impacts Three-Dimensional Developing Human Engineered Cardiac Tissue Functionality", TISSUE ENGINEERING PART A, vol. 28, no. 23-24, 1 December 2022 (2022-12-01), US, pages 990 - 1000, XP093290902, ISSN: 1937-3341, DOI: 10.1089/ten.tea.2022.0107 *
NAVAEE FATEMEH, KHORNIAN NILOOFAR, LONGET DAVID, HEUB SARAH, BODER-PASCHE STEPHANIE, WEDER GILLES, KLEGER ALEXANDER, RENAUD PHILIP: "A Three-Dimensional Engineered Cardiac In Vitro Model: Controlled Alignment of Cardiomyocytes in 3D Microphysiological Systems", CELLS, vol. 12, no. 4, pages 1 - 15, XP093290906, ISSN: 2073-4409, DOI: 10.3390/cells12040576 *

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